About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

January 31, 2011

Sanofi's PARP1 Inhibitor Misses

Posted by Derek

Past results, they tell you, are no guarantee of future performance. Sanofi-Aventis is ready to tell you all about that after the results of a Phase III trial of their recently acquired oncology drug, iniparib (BSI-201). This had shown very strong results in Phase II against "triple-negative" breast cancer, but it appears to have missed two survival endpoints in a larger trial. Sanofi bought BiPar, the company that had been developing the drug, a little less than two years ago.

Iniparib's a small molecule indeed - small enough that its systematic name can be immediately parsed by any sophomore chemistry student. It's 4-iodo-3-nitrobenzamide; it's the sort of thing you can order out of a catalog. But it's also an inhibitor of poly-(ADP-ribose) polymerase I (PARP1), and it's the first compound of that class to get this far in the clinic. PARP1 is part of a DNA repair pathway, although it's not on the front line. That would be homologous recombination, which is the pathway that needs the well-known BRCA to function. The idea has been that since so many aggressive breast cancers are deficient in BRCA, that they'd be especially sensitive to something that targeted PARP as well - they should accumulate so many DNA breaks that they'd be unable to replicate.

That's a perfectly reasonable theory. But it doesn't seem to have yielded perfectly reasonable results in this case. Problem is, PARP1 has a lot of functions in the cell, and inhibiting the lot of them all at once may not be such a good idea. One possibility is that effects on the Akt pathway might boomerang and reduce the effectiveness of therapy.

More broadly, this is yet another illustration of the perils of Phase II data. And it does make a person think about the idea of tightening up the endpoints of such trials even more. Problem is, you often don't get good survival numbers until Phase III, anyway, by which time you've spent the money. Like Sanofi-Aventis is spending it now. Let's hope that one of the other indications for the drug works out better.

Update: here's a rundown on competition in this field. The next round of clinical data will be quite interesting. . .

Iniparib is not as potent as other drug that is coming down the pike (Abbott, Merck, AZ etc.) in this area. I do not understand the significance of taking a weak inhibitor for this important area. Otherwise a very doable and an important target that hold lot of promise, if POC is to be believed..

I'm just catching up on the results of this latest trial but this apparent crash caught me by surprise and is very disappointing. The earlier studies appeared to me to be quite encouraging -- esp. given the difficulty of treating triple-negative breast cancer. :[

Reading between the lines, it appears they have loosened the inclusion criteria going from phase II to phase III in order to get approval in a broader class (larger market), but instead shot themselves in the foot.

you write:
".. Problem is, you often don't get good survival numbers until Phase III, anyway.."

Many cancer therapeutics get to market without showing any improvement in survival. They're approved on surrogate endpoints (shrinking a lump, delayed progression...). Delta survival emerges (or fails to emerge) after approval. That's why approval should be contingent on a survival results in "Phase IV" data collected from real patients after release.

Not sure why the results are being published as a flop. As wwjd discusses, the strong phase 2 results were built on an approval strategy as a 2nd or 3rd line therapy. Those results appeared positive, as would have been predicted from the strong phase 2 findings. The failure certainly is Sanofi's, more than Iniparib's. Despite clinical potential, it might be tough now to wipe away the stigma of what has been labelled as a failed trial in knee-jerk reactions like this column.